Clinical and pharmacological studies have shown that 5-HT1A agonists and partial agonists are useful in the treatment of a range of affective disorders such as generalised anxiety disorder, panic disorder, obsessive compulsive disorder, depression and aggression.
It has also been reported that 5-HT1A ligands may be useful in the treatment of ischaemia.
An overview of 5-HT1A antagonists and proposed potential therapeutic targets for these antagonists based upon preclinical and clinical data are presented by Schechter et al. Serotonin 1997, Vol. 2, Issue 7. It is stated that 5-HT1A antagonists may be useful in the treatment of schizophrenia, senile dementia, dementia associated with Alzheimer's disease, and in combination with SSRI antidepressants also to be useful in the treatment of depression.
5-HT reuptake inhibitors are well-known antidepressant drugs and useful for the treatment of panic disorders and social phobia.
The effect of combined administration of a compound that inhibits serotonin reuptake and a 5-HT1A receptor antagonist has been evaluated in several studies mis, R. B. et al. Eur., J. Pharmacol. 1987, 143, p 195-204 and Gartside, S. E. Br. J. Pharmacol. 1995, 115, p 1064-1070, Blier, P. et al. Trends Pharmacol. Sci. 1994, 15, 220). In these studies it was found that combined 5-HT1A receptor antagonists and serotonin reuptake inhibitors would produce a more rapid onset of therapeutic action.
Dopamine D4 receptors belong to the family of dopamine D2-like receptors which is considered to be responsible for the antipsychotic effects of neuroleptics. Dopamine D4 receptors are primarily located in areas of the brain other than striatum, suggesting that dopamine D4 receptor ligands have antipsychotic effect and are devoid of extrapyramidal activity.
Accordingly, dopamine D4 receptor ligands are potential drugs for the treatment of psychosis and positive symptoms of schizophrenia and compounds with combined effects at dopamine D4, and serotonergic receptors may have the further benefit of improved effect on negative symptoms of schizophrenia, such as anxiety and depression, alcohol abuse, impulse control disorders, aggression, side effects induced by conventional antipsychotic agents, ischaemic disease states, migraine, senile dementia and cardiovascular disorders and in the improvement of sleep.
Dopamine D3 receptors also belong to the family of dopamine D2-like receptors. D3 antagonistic properties of an antipsychotic drug could reduce the negative symptoms and cognitive deficits and result in an improved side effect profile with respect to EPS and hormonal changes.
Accordingly, agents acting on the 5-HT1A receptor, both agonists and antagonists, are believed to be of potential use in the therapy of psychiatric and neurological disorders and thus being highly desired. Furthermore, antagonists, at the same time having potent serotonin reuptake inhibition activity and/or D4 and/or D3 activity, may be particularly useful for the treatment of various psychiatric and neurological diseases.
Previously, closely related structures have been reported:    WO 9955672 discloses a general formula in which indole derivatives having 5-HT1A receptor and D2 receptor affinity are included    EP 900792 discloses a general formula in which indole derivatives are embraced as 5-HT1A and 5-HT1D as well as D2 receptor ligands.
It has now been found that a class of indole derivatives is particularly useful as 5-HT1A ligands. Furthermore, it has been found that many of these compounds have other highly beneficial properties as e.g. potent serotonin reuptake inhibition activity and/or affinity for the D4 receptor.